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Enlarged Cell-associated Proteoglycans Abolish E-Cadherin Functionality in Invasive Tumor Cells¹

Laboratories of Molecular Cell Biology [K. L. V, A. A. K., F. M. v. R.], University of Ghent, B-9000 Ghent, Belgium, Experimental Cancerology [J. J. D., E. A. B., M. M. M.], University of Ghent, B-9000 Ghent, Belgium, Pharmaceutical Technology [G. M. R. V], University of Ghent, B-9000 Ghent, Belgium

⁴ To whom requests for reprints should be addressed, at Laboratory of Molecular Cell Biology, University of Ghent, Ledeganckstraat 35, B-9000, Belgium. F. M. V. is Research Director of the Belgian National Fund for Scientific Research (NFWO).

Mouse and dog epithelial cell lines, expressing high levels of the Ca²⁺-dependent cell-cell adhesion molecule E-cadherin in vitro, generated invasive and metastatic tumors in athymic mice. From these tumors, neoplastic cell lines were isolated. All ex vivo isolates retained high expression levels of E-cadherin at their surface. Nevertheless, some showed a fusiform morphotype, were defective in Ca²⁺-dependent cell aggregation, and were invasive in vitro, indicating that E-cadherin was not functional. Cell-associated proteoglycans were found to be enlarged in these variants as compared to their counterparts with functional E-cadherin. Treatment of the cells with the drug 4-methylumbelliferyl β-D-xyloside specifically reduced the amount and size of cell-associated proteoglycans. This same drug induced an epithelial morphotype, increased Ca²⁺- and E-cadherin-dependent cell aggregation, and abrogated invasiveness without influencing E-cadherin expression levels. Our results indicate that enlarged proteoglycans can prevent the homophilic binding of E-cadherin, probably by steric hindrance. This is one more mechanism by which carcinomas may counteract invasion-suppressor genes and acquire malignancy.

¹ This research was supported by the Algemene Spaarbank en Lijfrentekas (ASLK), Fonds voor Geneeskundig Wetenschappelijk Onderzoek (FGWO), and Nationale Loterij, Belgium, and by the Belgian Cancer Association.

² Present address: Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 368, New York, NY 10021.

³ A. A. K. is a fellow of the Belgian Instituut voor Onderzoek in Nijverheid en Landbouw (IWONL).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/15/93. Accepted 1/ 5/94.

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